Molecular Basis for Anticancer and Antiparasite Activities of Copper-Based Drugs

Abstract

Herein, some possible determining factors in the mechanism of action of some copper(II) metal complexes toward vital biomolecules implicated in cell cycle are discussed. Based on indole derivatives already tested in clinical trials as anticancer therapeutics, some ligands containing oxindole moieties were designed, synthesized, and afterward metallated. Improved biological activity of the resulting complexes was achieved by the introduction of positive charge, and the tuning of compound geometry by specific conformation associated with such ligands. The corresponding copper(II) complexes are capable of generating reactive oxygen species (ROS) in the presence of hydrogen peroxide, and oxidizing carbohydrates, lipids, and proteins. Further, they can bind and cause double-strand DNA cleavage in an oxidative process modulated by the ligand. As cationic lipophilic species, they can enter the cell, and efficiently induce apoptosis in different tumor cells, having DNA and mitochondria as main targets. Additionally, this kind of metal-based compounds can inhibit specific proteins, implicated in topological changes of DNA, such as topoisomerases, or in the control of cell cycle, such as kinases. In both cases, particular features of the ligand were shown to be important for better inhibition effectiveness, besides the redox properties of the central metal, since analogous zinc(II) complexes also exhibited significant activity. Finally, these complexes showed also to be efficient trypanosomicidal compounds, with low IC50 against different forms of T. cruzi. Theoretical simulations, using DFT, molecular dynamics, and molecular docking, helped to better understand the biological activity of such class of compounds, giving rational support for the experimental data.